The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference, and for convenience are referenced in the following text by author and are listed alphabetically by author in the appended bibliography.
The ability to visualize an object (or picture) as a set of parts and construct a replica of the object from those parts is known as visuospatial constructive cognition. Neuroanatomical studies in humans and animals suggest that neurons in the posterior parietal cortex are critical for this process (Capruso et al., 1995). This cognitive function is likely mediated by a network of neurons capable of parallel processing. The molecular mechanisms underlying development of these networks, however, are not understood.
Williams syndrome (WS) is a complex developmental disorder that includes a specific cognitive profile (WSCP) characterized by relative strength in language and auditory rote memory and pronounced weakness in visuospatial constructive cognition (Udwin et al., 1987; Morris et al., 1988; Dilts et al., 1990; Bellugi et al., 1994; Mervis and Bertrand, in press; Mervis et al., in press). Additional features of WS include congenital heart and vascular disease, dysmorphic facial features, infantile hypercalcemia, mental retardation, and a characteristic personality. Most individuals with WS have mild or moderate mental retardation (mean IQ ranging from 55-60), but some have borderline normal intelligence or severe mental retardation. The characteristic personality includes excessive friendliness, loquaciousness, oversensitivity to the feelings of others, and extreme anxiety to please. This combination of features results in a remarkable phenotype that is readily distinguished from other disorders involving mental retardation. The incidence of WS is estimated to be 1 in 20,000 live births.
The visuospatial constructive cognitive deficit observed in WS is best demonstrated by tasks involving pattern construction. Performance of these tasks depends on an individual's ability to see an object in terms of a set of parts specified by the researcher and then use those parts to construct a replica of the pictured object. Specifically, individuals are shown a picture of a block design and must construct the corresponding pattern using cubes of varying colors and designs. Individuals with WS typically have difficulty constructing even simple patterns, such as a checkerboard consisting of four cubes. As a result, individuals with WS have marked difficulty in tasks involving the use of a pattern to assemble an object (e.g. building a model or assembling a simple piece of furniture).
Approximately 77% of individuals with WS have clinically apparent supravalvular aortic stenosis (SVAS), an obstructive vascular disease (Lowery et al., 1995). SVAS can be inherited as part of WS or as an isolated, autosomal dominant trait (Curran et al, 1993; Ewart et al., 1993b; Morris et al., 1993; Ewart et al., 1994). SVAS may be associated with some connective tissue abnormalities seen in WS, but other WS features are not observed. In particular, autosomal dominant SVAS is not associated with impaired visuospatial constructive cognition. Recently, genetic linkage and mutational analyses were used to show that mutations in elastin (ELN) cause autosomal dominant SVAS (Ewart et al., 1993a; Curran et al., 1993; Morris et al., 1993; Ewart et al., 1994). Known SVAS-associated mutations in ELN include a translocation, an intragenic deletion, and missense and nonsense mutations (Curran et al., 1993; Olson et al., 1995; unpublished data).
Because there is a phenotypic link between SVAS and WS, it was hypothesized that mutations involving ELN might also contribute to WS. It was discovered that WS results from submicroscopic deletions of chromosome 7q11.23 (Ewart et al., 1993a). Inherited or de novo deletion of one ELN allele was identified in 239 of 240 WS individuals (Ewart et al., 1993a; Lowery et al., 1995; and our unpublished data). These data indicated that ELN mutations cause isolated, autosomal dominant SVAS and that hemizygosity at the ELN locus is responsible for vascular pathology in WS. ELN hemizygosity may also account for some connective tissue abnormalities observed in individuals with autosomal dominant SVAS or WS, including premature aging of skin, some WS facial features, diverticulosis of the bladder and colon, hoarse voice, hernias and joint abnormalities. ELN mutations, however, do not account for all features of WS and are not the cause of impaired visuospatial constructive cognition. Because genomic deletions responsible for WS extend well beyond the ELN locus (unpublished data), it was hypothesized that WS is a contiguous gene deletion syndrome (Ewart et al., 1993a).
Here is reported the identification and characterization of two families with a partial WS phenotype, consisting of SVAS, some WS facial features, and impaired visuospatial constructive cognition, but lacking other features of this disorder. Affected members of these families harbor smaller chromosomal deletions (83.6 and .about.300 kb) than those identified in individuals with classic WS (&gt;500 kb), an observation that supports the hypothesis that WS is a contiguous gene deletion syndrome (Ewart et al., 1993a; Gilbert-Dussardier et al., 1995). DNA sequence analyses of the 83.6 kb deletion region have revealed, in addition to ELN, LIM-kinasel (LIMK1), a gene which encodes a protein kinase with LIM domains (Mizuno et al., 1994; Bernard et al., 1994). No other genes were identified in the region. Northern and in situ hybridization analyses indicate that LIMK1 is strongly expressed in discrete regions of the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data indicate that LIMK1 hemizygosity contributes to impaired visuospatial constructive cognition in WS.